Active materials have been used throughout much of human history. In the modern era, significant use has been made of active materials extracted from natural sources or synthesised, whether to replace the natural source of the material or to generate new active analogues thereof or to generate new active materials. Such active materials may comprise a variety of morphologies including amorphous, crystalline, including single crystal, polymorphic, ionic crystalline and cocrystal morphologies. As is well understood in the art, there are many ways of manufacturing active materials including precipitation from solution, crystallisation from melts or solutions etc, although the preparation of cocrystalline materials may not be necessarily straight forward as is described in greater detail below.
The physiochemical properties of different morphological forms of the same active material may have a significant effect on inter alia the processability, deliverability and effectiveness of the active materials. A consequence of this is that the identification of different morphological forms of active materials with their corresponding physiochemical properties and effectiveness as an active material places a significant cost burden on researchers and developers of such materials, especially, but not solely, in the pharmaceutical industries. This, in turn, creates significant pressure to obtain intellectual property protection for active materials to ensure the costs of research and development may be recovered over the period of such protection. The inability to obtain intellectual property protection for new active materials may result in such materials not being developed at all.
The lapse of intellectual property protection for existing morphological versions of active materials or the potential lack of such protection for new active materials or for new morphological versions of known active materials, whether owing to the similarity to earlier versions of such active materials or for other reasons, has recently led to a significant interest in the development of cocrystalline active materials, which, owing to the novel molecular combinations and different physiochemical properties exhibited as compared to the corresponding free form of the active material, may be capable of being protected by intellectual property rights.
Cocrystals per se have been known and studied for many years. It is generally understood that cocrystals exhibit long-range order and the components thereof interact via intermolecular interactions including non-covalent interactions such as hydrogen and/or halogen bonding, π interactions, ionic interactions, and van der Waals interactions. These intermolecular interactions, and the resulting crystal structures, generate physical and/or chemical properties, for example melting point, solubility, chemical stability, and mechanical properties, which differ from the properties of the individual components. Notwithstanding this, although the term “cocrystal” is generally understood in the art, there is no current agreed definition of that term, as is exemplified in a paper entitled “Polymorphs, Salts, and Cocrystals: What's in a Name?”, Cryst. Growth Des., 2012, 12, 2147-2152, which was prompted by draft guidance issued by the United States Food and Drug Administration (FDA) relating to the definition of cocrystals for regulatory purposes. The authors of that paper considered the FDA guidance was too limited and proposed their own definitions of the term “cocrystal”, the broadest version of which reads:                “cocrystals are solids that are crystalline single phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio”.        
The multicomponent nature of cocrystals has previously been recognised as evidenced by paper entitled “The Salt-Cocrystal Continuum: The Influence of Crystal Structure on Ionisation State”, Molecular Pharmaceuticals, Vol 4, No 3, 323-338. This paper notes that both salts and cocrystals are multicomponent and that, depending on a number of factors, in addition to salts and cocrystals a continuum containing both ionic crystalline species and cocrystalline species may exist.
Whatever definition of “cocrystal” may eventually be adopted, as used in this specification it is intended the term be interpreted broadly and not be artificially restricted by definitions such as that proposed by the FDA, which, as identified by the authors of the paper, are relatively restricted.
As mentioned above, cocrystals may be made in a variety of ways similarly to other crystalline forms of active materials, although such methods may not be without difficulties when applied to cocrystal manufacture. Methods of cocrystallisation include slow evaporation of a solvent from a solution containing cocrystal components; cocrystallising from a slurry of the components; cocrystallising from a melt; cocrystallising in a supercritical fluid; or wet or dry grinding of the components together. In the latter instance, the application of mechanical energy to the components appears to be a prerequisite in many methods. Examples of some of these methods may be found in EP 2170284, EP 2361247, US 2007/0287184, US 2009/0054455, US 2010/0204204, U.S. Pat. No. 7,927,613 and WO 2011/097372 and in “The role of mechanochemistry and supramolecular design in the development of pharmaceutical materials”, CrystEngComm, 2012, 14, 2350-2362. More specifically, for example, US 2009/0054455 describes the synthesis of aripiprazole/fumaric acid cocrystals by dissolving aripiprazole and fumaric acid in a suitable solvent to form a clear solution of the components and then adding an anti-solvent to precipitate the cocrystals; and EP 2170284 describes using supercritical or liquefied gas to prepare a cocrystallisation medium containing a dissolved API and a dissolved co-former, cocrystals being recovered from the supercritical or liquefied gas by depressurisation.
The prior art methods for producing cocrystals are usually practised on a relatively small scale and scaling up such methods may present significant difficulties. For example, solvent-based methods would require substantial volumes of solvents resulting in lower yields of active crystalline materials. Mechanical or pressure methods would require relatively high capital investment.
There is a clear need for a simple, effective method of making active crystalline materials and, in particular, of making active multicomponent crystalline materials, and, especially, active cocrystalline materials.